Roxindole, a potential antidepressant. I. Effect on the dopamine system

Roxindole (EMD 49980, 5-hydroxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl(1))-butyl(1)]-indole mesylate), a selective dopamine autoreceptor agonist and a potential antipsychotic drug, shows a clinical antidepressant efficacy. The present paper examined the neuropharmacological profile of roxindole in rats (male Wistar) and mice (male Albino Swiss) in respect of its influence on dopamine system. Used in low doses, roxindole decreased the locomotor activity, but in higher ones it did not induce a locomotor hyperactivity or stereotypy. It antagonized the amphetamine-induced hyperlocomotion, the amphetamine- or apomorphine-induced stereotypy, apomorphine climbing behaviour and reserpine-induced akinesia. The quinpirole-induced hyperlocomotion was inhibited by roxindole. When given alone, the drug in question, did not induce the catalepsy, but antagonized the catalepsy induced by haloperidol, spiperone and fluphenazine. The immobility time in the forced swimming test was reduced. Like typical antidepressants, roxindole given repeatedly (twice daily, 14 days) increased the hyperlocomotion induced by D-amphetamine. The results described above indicate that roxindole may have an antidepressant and antiparkinsonian activity and should be devoid of extrapyramidal side-effects.     

Proceedings: On the central action of nomifensine (author's transl)

The central action of nomifensine (NF), a new antidepressive drug, was studied in rats and mice. NF stimulates locomotor activity in normal animals as well as in animals whose motor activity has been depressed by reserpine, alpha-methyltyrosine (alpha-MT), bis-(4-methyl-1-homopiperazinyl-thiocarbonyl)-disulfide (Fla-63) or phenoxybenzamine. The sedation produced by alpha-MT plus reserpine or by spiroperidol is not affected by NF. NF induces stereotypy in the rat and antagonizes the catalepsy induced in the rat by neuroleptics, pilocarpine and arecoline. The catalepsy induced by alpha-MT plus reserpine is not influenced. NF elevates the brain levels of serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in the rat. These and previous results indicate that the profile of action of NF differs both from that of known tricyclic antidepressive drugs and that of dopaminergic stimulants.     

Association of the platelet Pl(A) polymorphism of glycoprotein IIb/IIIa and the fibrinogen Bbeta 448 polymorphism with myocardial infarction and extent of coronary artery disease

Decrease of olfactory function in patients with Parkinson's disease (PD) has been reported by several authors. The current study investigated olfaction in PD patients using olfactory event-related potentials (OERPs) as an electrophysiologic correlate of olfactory function in combination with psychophysical testing. A specific focus was the influence of antiparkinsonian drugs. We investigated PD patients treated with antiparkinsonian drugs (n = 13) and PD patients who received no pharmacologic treatment (n = 18). They were compared to age- and sex-matched control subjects (n = 38). To obtain OERPs, stimulants were chosen to stimulate specifically the olfactory nerve (2.1 ppm vanillin, 0.8 ppm H2S). In addition, chemosomatosensory event-related potentials were recorded after trigeminal stimulation with 52% v/v CO2. Moreover, the subjects' ability to identify and to discriminate odorants was tested by means of a "squeeze bottle" technique. The study yielded the following major results: (1) Odor identification was impaired in PD patients. It was not influenced by treatment with antiparkinsonian drugs. (2) The OERP latencies were prolonged in both PD patients taking and not taking antiparkinsonian drugs; however, this effect was more pronounced in PD patients taking antiparkinsonian drugs. (3) The intranasal chemosensory trigeminal system seemingly was neither affected by the neuronal degeneration seen in PD nor by treatment with antiparkinsonian drugs.     

Postnatal development of dopaminergic and cholinergic catalepsy in the rat

The cataleptic response to various doses of the dopamine-receptor antagonist spiperone and the cholinergic agonist pilocarpine was investigated in rats of different ages. Spiperone produced catalepsy in rats 1, 5 and 10 days old, and also in adults. Pilocarpine produced catalepsy in 15- and 20-day old rats, as well as in adults, but not in 10-day old animals. These results suggest that dopaminergic neurons involved in catalepsy are already functional in neonates. Cholinergic substrates of catalepsy, on the other hand, appear to reach functional maturity after the second week of life.     

Antiparkinsonian drug abuse: eight case reports

Although abuse of antiparkinsonian drugs has rarely been reported in this country, there is evidence that it is more widespread than has generally been believed. The author reports eight cases in which abuse of the drugs was suspected. He emphasizes the need for increased awareness among physicians of the potential for abuse of antiparkinsonian agents and greater caution in prescribing them.     

The quality of the discharge planning process: the effect of a liaison nurse

Nitric oxide (NO) in brain has been implicated in neuronal regulatory processes and in neuropathologies. Previously we showed that NO modified quinpirole-induced yawning, a behavioral measure of dopamine (DA) D3 receptor activation in rats. The aim of this study was to characterize the effect of nitro-L-arginine methyl ester HCl (NAME) and L-arginine HCl on reactivity of rats to the DA D1 receptor agonist SKF 38393 and DA D1 antagonist SCH 23390 in intact and neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats (134 micrograms of base ICV at 3rd day after birth). L-arginine HCl (300 mg/kg i.p.) increased the oral activity response in 6-OHDA-lesioned rats, like SKF 38393, and induced catalepsy in intact control rats, like SCH 23390. In contrast, NAME had no effect on oral activity or catalepsy, but fully attenuated SKF 38393-induced oral activity. These findings indicate that L-arginine HCl has no apparent effect at the DA D1 receptor, but that NAME is effective in attenuating a DA D1 agonist-induced effect. Consequently NO may be an intracellular second messenger for supersensitized receptors associated with DA D1 agonist-induced oral activity.     

Effect of morphine-induced catalepsy, lethality, and analgesia by a benzodiazepine receptor agonist midazolam in the rat

Previously we have shown that intrathecal administration of midazolam can increase or decrease morphine-induced antinociception, depending upon relative concentration of these drugs by modulating spinal opioid receptors, and it also can inhibit morphine-induced tolerance and dependence in the rat. Now we report that midazolam also influences catalepsy, lethality, and analgesia induced by morphine in the rat. In the acute treatment, animals were first treated with saline or midazolam (0.03 to 30.0 mg/kg, b.wt., IP), and 30 min later with a second injection of saline or morphine (1.0 to 100.0 mg/kg, b.wt., SC). The catalepsy was measured 60 min after the second injection and lethality was checked after 24 h. Midazolam injection increased the morphine-induced catalepsy and lethality. In the chronic treatment, animals were injected with two injections daily for 11 days. The first injection consisted of saline or midazolam (0.03 to 3.0 mg/kg, b.wt., IP), and 30 min later with a second injection of saline or morphine (10.0 mg/kg, b.wt., IP) was given. Lethality, antinociception, and body weight were measured. Chronic morphine treatment also increased lethality in a dose-dependent manner. Chronic treatment with midazolam and morphine increased the antinociception on day 11, as measured in the tail-flick and hot-plate tests. Midazolam administration also prevented the morphine-induced weight loss. These results suggest a strong interaction between midazolam and morphine in altering catalepsy, lethality, and analgesia in rat.     

Arginine-aspartate and haloperidol-induced neurobehavioral effects in the rat

This study determined the effects, in the rat, of 8-day treatment with arginine-aspartate on haloperidol-induced catalepsy, decrease of locomotor activity and change of striatal dopamine, homovanillic acid (HVA) and dihydroxy-phenylacetic acid (DOPAC) content. Arginine-aspartate was able to attenuate the haloperidol-induced decrease of locomotor activity and to significantly reduce the catalepsy. Moreover, arginine-aspartate treatment itself increased striatal dopamine content and produced a significant decrease of the HVA/dopamine ratio. Pretreatment with arginine-aspartate was able to partially counteract the haloperidol-induced changes of dopamine metabolism: the haloperidol-induced increases of the DOPAC/dopamine and HVA/dopamine ratios were significantly reduced in arginine-aspartate- pretreated rats. These results suggest that the action of arginine-aspartate on haloperidol-induced neurobehavioral effects is probably mediated by interference with striatal dopaminergic innervation.     

Some behavioral effects of 1,3-di-o-tolylguanidine, opipramol and sertraline, the sigma site ligands

1,3-Di-o-tolylguanidine (DTG), opipramol (OPI) and sertraline (SER), sigma site ligands, were studied in Wistar rats and Albino Swiss mice, mainly with regard to their interaction with dopamine drugs. DTG and SER (at the highest doses only) decreased the spontaneous locomotor activity. DTG did not change the amphetamine locomotor hyperactivity, while OPI and SER decreased it. The amphetamine stereotypy was slightly increased (prolonged) by all the three drugs. OPI antagonized the locomotor hyperactivity, stereotypy, aggression and climbing, all those being induced by apomorphine; DTG inhibited only the aggression, while SER-the aggression and climbing (the latter was also inhibited by paroxetine, which showed no affinity for sigma sites). DTG and SER (but not paroxetine) were able to increase the locomotor hyperactivity induced by quinpirole. That effect was antagonized by OPI which-when given alone-did not affect the quinpirole hyperlocomotion. The reserpine-induced akinesia was not affected by DTG, OPI or SER; the L-DOPA hyperactivity in reserpinized rats was changed (increased) by DTG only. DTG and SER (also paroxetine and citalopram), but not OPI, increased the cocaine locomotor hyperactivity. All the three sigma ligands given alone did not evoke catalepsy; the haloperidol- and spiperone-induced catalepsy was attenuated by DTG and OPI, but increased by SER. The MK-801-induced hyperactivity was decreased by DTG, but increased by OPI and SER. In the forced swimming test, only DTG slightly reduced the immobility time; the reduction of the immobility time induced by MK-801 was not changed by DTG, but increased by OPI and SER. Only DTG evoked a dose-dependent decrease in the body temperature, which was not changed by rimcazole. The above results indicate that the sigma site ligands studied differ in their pharmacological profile; however, it is still difficult to determine unequivocally whether they show agonistic or antagonistic properties.     

Electrophysiological pharmacology of the autoreceptor-mediated responses of dopaminergic cells to antiparkinsonian drugs

It is generally accepted that the dopamine receptor ligands currently used in the treatment of parkinsonian symptoms mainly stimulate dopamine (DA) receptors of the D2 family to produce beneficial effects. Although several animal models can provide useful indications on the activity of the antiparkinsonian drugs in the brain, the specific cellular sites and the mechanism of action of these therapeutic agents are not completely known. In this article, Nicola Mercuri, Antonello Bonci and Giorgio Bernardi suggest that the electrophysiological effects of antiparkinsonian drugs on nigral dopaminergic cells are related to their clinical efficacy. In addition, they report that the stimulation of the D2 'autoreceptors' located on the residual dopamine-containing cells is implicated in the therapeutic response elicited by dopamine receptor agonists in parkinsonism. Thus, an electrophysiological approach, which can give basic information regarding the actions of direct and indirect DA receptor agonists on the dopaminergic neurones, might be relevant for the evolution of the pharmacological strategies in Parkinson's disease.     

Severity, time, and beta-adrenergic receptor involvement in surgery-induced immune alterations

It is known that calcium channel blockers induce Parkinsonism. In this study, amlodipine-, diltiazem-, and verapamil-induced catalepsy was investigated in mice. All of these three calcium channel blockers induced catalepsy. Dopamine D1, D2, and mACh receptor occupancies were estimated under the same conditions, and the affinities of these drugs for each receptor were also estimated in vitro. Intensity of catalepsy was predicted by dopamine D1, D2, and mACh receptor occupancies with the dynamic model which had already been constructed and was compared with the observed values. The predicted and the observed values were comparable (r = 0.98, p < 0.001). In conclusion, the dynamic model considering D1, and D2, and mACh receptor occupancy may be useful for quantitative prediction of drug-induced catalepsy.     

Polymorphisms in the human CC chemokine receptor-3 gene

In the present study we investigated the chronopharmacological dependence of dose-dependent hypotensive and cardiochronotropic effects of the imidazoline-like drugs (clonidine, rilmenidine and moxonidine) in stroke-prone spontaneously hypertensive rats (SHR-SP), using radio-telemetric system (Data Sciences, USA). The 24-h blood pressure, heart rate and locomotor activity profiles showed peak values during the rats' active phase during the night period. The degree of hypotensive and bradycardic effects of all drugs were most evident at this time and occurred in the absence of a change in locomotor activity. These studies show that clonidine, rilmenidine and moxonidine decrease blood pressure and heart rate in a time-dependent manner in SHR-SP. It was demonstrated that the degree and duration of hypotensive action of imidazoline-like drugs vary with the time of drug administration.     

Effects of the dopamine antagonist PD 152255 on juvenile rats' responses to dorsal stimulation, the transport response and related behaviors.

The authors gave 23- and 40-day-old rats doses of the dopamine D? antagonist PD 152255 and tested them on transport response intensity, vertical cling catalepsy duration, and dorsal immobility duration. Administration of PD 152255 resulted in dose-dependent increases in transport response intensity in 40-day-old rats but was without effect in 23-day-old rats. Administration of PD 152255 caused increases in dorsal immobility durations in both 23- and 40-day-old subjects. The drug was without effect on vertical cling catalepsy. Results are discussed with respect to the role of D? receptors in the transport response and the nature of D?-D? receptor interactions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Covariation bias in phobic women: the relationship between a priori expectancy, on-line expectancy, autonomic responding, and a posteriori contingency judgment

The behavioral effects of cabergoline, pergolide and bromocriptine were investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity, as evidenced by irritability, excitability and aggressiveness. All three drugs improved the parkinsonism in a dose-dependent fashion following a single injection. Among the three dopamine (DA) receptor agonists used, the antiparkinsonian effect of pergolide was the strongest and had an immediate effect, while cabergoline showed the longest duration of the antiparkinsonian effect and was least potent in inducing hyperactivity.     

The role of catecholamines, acetylcholine and cholinesterase activity in the development of the cataleptic action of triftazin following repeated administration

Catalepsy occurring in rats in a singular and repeated introduction of triftasine has a manifold mechanism, the main components of which are related to the metabolism of dophamine, acetylcholine and cholinesterase activity. A change in the intensity of catalepsy in a multiple introduction of the preparation is due mainly to cholinergic influences.     

Some behavioral effects of CNQX AND NBQX, AMPA receptor antagonists

CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) and NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline), two competitive AMPA (non-NMDA glutamate) receptor antagonists, as well as their interaction with CGP 37849, a competitive NMDA receptor antagonist, were studied in rats and mice. CNQX and NBQX inhibited the locomotor activity of naive rats. No symptoms of behavioral excitation were observed. CGP 37849 induced locomotor hyperactivity which was reduced by CNQX and NBQX. In monoamine-depleted rats (pretreated with reserpine + alpha-methyl-p-tyrosine), none of the two quinoxalines nor CGP 37849 antagonized akinesia. The antiakinetic effect of L-DOPA was increased by CGP 37849, but not by CNQX or NBQX. The latter action of CGP 37849 was decreased by CNQX and NBQX. The antiakinetic effect of clonidine was not changed by CNQX. The locomotor hyperactivity induced by apomorphine or cocaine was not modified by CNQX. Neither of the quinoxalines changed the catalepsy induced by haloperidol or spiperone. The fluphenazine catalepsy was slightly decreased by CNQX and increased by NBQX. CNQX and NBQX were inactive in the forced swimming test; CNQX (but not NBQX) increased the CGP 37849-induced reduction of the immobility time. CNQX decreased the muscle tone of hind limbs in naive and monoamine-depleted rats. The obtained results indicate that the AMPA receptor antagonists differ in their neuropharmacological profile from CGP 37849, an NMDA receptor antagonist. There is no positive cooperation (except for the forced swimming test) between NMDA and AMPA receptor antagonists; on the contrary, an antagonistic between them has been observed.     

Neurosurgery at the University of Virginia

Although recently developed drugs have brought significant improvement, the treatment of psychotic disorders still presents serious drawbacks. Because inherent complexity and lack of satisfactory understanding of the underlying pathophysiology impose limits for rational drug design, resourceful approaches in the search for antipsychotics are pertinent. This article reports pharmacological properties of alstonine, a heteroyohimbine-type alkaloid, which exhibited an antipsychotic-like profile, inhibiting amphetamine-induced lethality, apomorphine-induced stereotypy, and potentiating barbiturate-induced sleeping time. Atypical features of alstonine were the prevention of haloperidol-induced catalepsy and lack of direct interaction with D1, D2 and 5-HT2A receptors, classically linked to antipsychotic mechanism of action.     

Developmental plasticity in the D1- and D2-mediation of motor behavior in rats depleted of dopamine as neonates

D1- and D2-like antagonist-induced catalepsy and dorsal immobility were studied in pups (Day 10) and weanlings (Days 20, 28, or 35) that received intraventricular injection of 6-OHDA (50 micrograms/hemisphere) or its vehicle solution or postnatal Day 3. The ability of the D1 of D2 antagonists to induce immobility differed as a function of the lesion condition and the age at the time of testing. Moreover, the two behavioral measures exhibited differences in their specific D1 and D2 receptor modulation. Administration of the D1 antagonist SCH 23390 (0.2 or 1.0 mg/kg) or the D2 antagonist clebopride (1.0, 10.0, or 20.0 mg/kg) led to catalepsy and dorsal immobility in intact rats, regardless of test age. Both antagonists induced catalepsy and dorsal immobility in rats depleted of DA when tested on Day 10. However, the effects of each antagonist in DA-depleted rats were ether negligible or significantly less than in controls when animals were tested as weanlings. These data suggest lesion-induced changes in the DA receptor modulation of motor behavior and that this plasticity requires more than a week to become apparent.     

Involvement of 5-HT6 receptors in nigro-striatal function in rodents

4-Amino-N-(2,4 bis-methylamino-pyrimidin-4-yl) benzene sulphonamide (Ro 04-6790) is a potent, selective and competitive antagonist for the 5-HT6 receptor which can be detected in the cerebro-spinal fluid (CSF) of rats following intraperitoneal administration. Since 5-HT6 receptor mRNA and 5-HT6 receptor-like immunoreactivity have been shown to be present in the striatum, the purpose of the present study was to evaluate the effect of 5-HT6 receptor antagonism on haloperidol- and SCH 23390-induced catalepsy in mice and on the turning behaviour of rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle. Ro 04-6790 (3, 10 and 30 mg kg(-1) i.p.) did not induce catalepsy and had no effect on catalepsy induced by either haloperidol or SCH 23390. Ro 04-6790 (3, 10 and 30 mg kg(-1) i.p.) did not itself induce rotational behaviour in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle nor did it affect the rotational behaviour induced by either L-Dopa or amphetamine. 5-HT6 receptor antagonism inhibited the rotational behaviour of 6-OHDA lesioned rats induced by treatment with the muscarinic antagonists scopolamine and atropine. The data support earlier conclusions from experiments with antisense oligonucleotides that the 5-HT6 receptor is involved in the control of acetylcholine neurotransmission in the rat brain.     

ECT in Parkinson's disease. Changes in motor symptoms, monoamine metabolites and neuropeptides

Electroconvulsive therapy (ECT) was given to 16 non-depressed, non-demented patients with advanced Parkinson's disease (PD). In all the patients an antiparkinsonian effect was seen, lasting for 18 months in one patient, 3-5 months in seven patients, and a few days to four weeks in eight patients. After ECT the levels of homovanillic acid and neuropeptide Y in cerebrospinal fluid (CSF) were significantly increased. The eight patients with long lasting motor improvement after ECT had significantly lower CSF-3-methoxy-4-hydroxyphenylglycol compared to the group with short lasting improvement. Five patients developed transitory mental confusion after ECT. In these patients, and in no others, a high albumin-ratio was found already before ECT was given - an indication of blood CSF barrier damage. Our results suggest that ECT is valuable in patients with drug refractory PD or PD with intolerance to antiparkinsonian drugs.